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Residual brain infection in murine relapsing fever borreliosis can be successfully treated with ceftriaxone
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Bergström)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Persson)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). (Bergström)
2008 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 44, no 3, 262-264 p.Article in journal (Refereed) Published
Abstract [en]

Like several other spirochetes, relapsing fever Borrelia can cause persistent infection of the central nervous system (CNS). By treating mice harboring residual Borrelia duttonii brain infection with the bacteriocidal, cell wall inhibiting antibiotic ceftriaxone, bacteria were cleared from the brain. This shows that the residual infection is not latent but actively growing.

Place, publisher, year, edition, pages
Elsevier, 2008. Vol. 44, no 3, 262-264 p.
Keyword [en]
Latent, Persistent, Ceftriaxone, Antibiotics, CNS infections, Meningitis
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-20789DOI: 10.1016/j.micpath.2007.11.002PubMedID: 18083325OAI: oai:DiVA.org:umu-20789DiVA: diva2:209548
Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2013-11-20Bibliographically approved
In thesis
1. Pathobiology of African relapsing fever Borrelia
Open this publication in new window or tab >>Pathobiology of African relapsing fever Borrelia
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Relapsing fever (RF) is a disease caused by tick- or louse-transmitted bacteria of the genus Borrelia. It occurs worldwide but is most common in Africa where it is one of the most prevalent bacterial diseases. The main manifestation is a recurring fever which coincides with massive numbers of bacteria in the blood. Severity ranges from asymptomatic to fatal.

RF is usually considered a transient disease. In contrast, B. duttonii causes a persistent, residual brain infection in C57BL/6 mice which remains long time after the bacteria are cleared from the blood. The host gene expression pattern is indistinguishable from that of uninfected animals, indicating that persistent bacteria are not recognized by the immune system nor do they cause noticeable tissue damage. This is probably due to the quite low number of bacteria residing in the brain. The silent infection can be reactivated by immunosuppression allowing bacteria to re-enter the blood. To investigate if the residual infection is in a quiescent state or if the bacteria are actively dividing, mice with residual brain infection were treated with the cell-wall disrupting antibiotic ceftriaxone, which is only active against dividing bacteria. Since all mice were cured by ceftriaxone we conclude that the bacteria are actively growing in the brain rather than being in a latent, dormant state. The brain is used as an immunoprivileged site to escape host immune defence and probably as a reservoir for bacteria.

RF is a common cause of pregnancy complications, miscarriage and neonatal death in sub-Saharan Africa. We established a murine model of gestational relapsing fever to study the pathological development of these complications. B. duttonii infection during pregnancy results in intrauterine growth retardation as well as placental damage and inflammation. Spirochetes cross the maternal-foetal barrier, resulting in congenital infection. Further, pregnancy has a protective effect, resulting in milder disease during pregnancy.

A clinic-based study to investigate the presence of RF in Togo was performed. Blood from patients with fever were examined for RF by microscopy, GlpQ ELISA and PCR. About 10% of the patients were positive by PCR and 13% had antibodies to GlpQ. Many RF patients originally had a misdiagnosis of malaria, which resulted in ineffective treatment. The inability of microscopic analysis to detect spirochetes demonstrates the need for tests with greater sensitivity. To provide simple, fast, cheap and sensitive diagnostics using equipment available in small health centres, a method based on enrichment of bacteria by centrifugation and detection by Giemsa staining was developed which detects <10 spirochetes/ml.

To study the phylogeny of RF, IGS and glpQ were sequenced and neighbor joining trees were constructed. B. persica and B. hispanica were distant from the other species iswhereas B. crocidurae appeared to be a heterogeneous species. B. duttonii is polyphyletic in relation to B. recurrentis suggesting that the two species may in fact be the same or have a polyphyletic origin.

Place, publisher, year, edition, pages
Umeå: Molekylärbiologi (Medicinska fakulteten), 2007. 92 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1137
Keyword
borrelia, persistence, meningitis, pregnancy, latency, immune privileged sites
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-1452 (URN)978-91-7264-430-4 (ISBN)
Public defence
2007-12-14, Major Groove, 6L, Inst. Molekylärbiologi, UMEÅ, 09:00 (English)
Opponent
Supervisors
Available from: 2007-11-26 Created: 2007-11-26 Last updated: 2009-05-27Bibliographically approved
2. Malaria and relapsing fever Borrelia: interactions and potential therapy
Open this publication in new window or tab >>Malaria and relapsing fever Borrelia: interactions and potential therapy
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infectious diseases such as malaria and relapsing fever borreliosis (RF), cause severe human mortality and morbidity in developing countries. Malaria, caused by Plasmodium spp. parasites, is estimated by the World Health Organization to cause 1.5-2.7 million deaths annually. RF, caused by Borrelia spirochetes, has the highest prevalence described for any bacterial disease in Africa, with infection outcomes ranging from asymptomatic to fatal. RF borreliosis manifests in humans as a recurring fever and with other symptoms very similar to those of malaria.

RF borreliosis has been regarded as a transient infection of the blood. However, B. duttonii exploits the brain as an immunoprivileged site escaping the host immune response while spirochetes in the blood are cleared. To investigate whether residual bacteria are dormant or actively dividing, mice with residual brain infection were administered ceftriaxone, a β-lactam antibiotic interfering with cell wall synthesis. Hence, it only affects actively dividing bacteria. Ceftriaxone eradicated brain RF infection in all treated mice, demonstrating that the bacteria are actively multiplying rather than in a dormant state. The findings support the therapeutic use of ceftriaxone for RF neuroborreliosis since penetration into cerebrospinal fluid is greater for ceftriaxone than for the often recommended doxycycline.

The clinical features of malaria and RF are similar and diagnosis is further complicated by the frequently occurring concomitant malaria-RF infections. Therefore, we established a mouse model to study the pathogenesis and immunological response to Plasmodium/Borrelia mixed infection. Interestingly, malaria was suppressed in the co-infected animals whereas spirochete numbers were elevated 21-fold. The immune response in the concomitantly infected mice was polarized towards malaria leaving the spirochetes unharmed. Mice with co-infections also exhibited severe anemia and internal damages, probably attributed to escalating spirochete numbers. A secondary malaria infection reactivated the residual brain RF infection in 60% of the mice. This highlights the importance of co-infections as diagnostic pitfalls as well as the need for novel treatment strategies.

Currently there is no commercial malaria vaccine and increasing drug resistance presents an urgent need for new malaria chemotherapeutics. Blood-stage malaria parasites are rapidly growing with high metabolic and biosynthetic activity, making them highly sensitive to limitations in polyamine supply. Disrupting polyamine synthesis in vivo with trans-4-methylcyclohexylamine (4MCHA) eradicated the malaria infection gradually, resulting in protective immunity. This leads the way for further biochemical and pharmacological development of the polyamine inhibitor 4MCHA and similar compounds as antimalarial drugs

Place, publisher, year, edition, pages
Umeå: Institutionen för molekylärbiologi, 2009. 84 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1258
Keyword
Malaria, Plasmodium, relapsing fever, Borrelia, persistent, concomitant infections, polyamines
National Category
Cell and Molecular Biology Microbiology in the medical area
Research subject
Molecular Biotechnology; Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-21845 (URN)978-91-7264-768-8 (ISBN)
Public defence
2009-05-15, Major groove, Umeå Universitet, Byggnad 6L, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2009-04-29 Created: 2009-04-20 Last updated: 2009-04-29Bibliographically approved

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Larsson, ChristerLundqvist, JennyBergström, Sven

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